Clinical depression is a devastating disorder. Treatments are available but recovery is usually slow. The effectiveness of drugs that block serotonin (5-HT) uptake suggests that an increase in 5-HT transmission is an important factor in recovery. It is puzzling however, that recovery takes weeks although uptake is rapidly blocked. This delay has been ascribed to a negative feedback mechanism whereby activation of autoreceptors suppresses 5-HT release. The proposed research will examine the factors controlling 5-HT release after administering uptake blockers. In vivo microdialysis will be used to test the hypothesis that the increase in extracellular 5-HT after acute administration of uptake blockers in restrained by autoreceptor-mediated inhibition of release. Selective and non-selective uptake blockers, will be administered to rats, and changes in extracellular 5-HT will be measured in three different brain sites. Autoreceptor antagonist drugs will be used to test the influences of negative feedback modulation of 5-HT release after uptake inhibition. Additional experiments will address the possibility that the delayed therapeutic effect of antidepressant drugs is correlated with gradual desensitization of autoreceptors and increased 5-HT release. Specifically, changes in extracellular 5-HT will be measured after chronic drug treatment, and the influence of autoreceptors and excitatory inputs evaluated using receptor antagonists. Related experiments will test the hypothesis that increased excitation of 5-HT neurons during behavioral arousal can offset the inhibitory influence of autoreceptors stimulation. This result would provide an experimental basis for the clinical observation that physical activity can speed recovery from depression. Understanding the factors influencing 5-HT release could aid in development of improved clinical treatment of depression.